Nuclear magnetic resonance systems and methods for noninvasive and in-vivo measurements using a unilateral magnet

ABSTRACT

An apparatus for non-invasive evaluations and in-vivo diagnostics includes an open magnet, an RF antenna, and an NMR analytics logical circuit communicatively coupled to the RF antenna, wherein the open magnet is shaped to generate a static magnetic field that extends unilaterally into an object or internal organ of a subject when the open magnet is positioned against or in proximity to the object or subject, the static and RF magnetic fields shaped to generate a sensitive volume within a target region. The RF antenna or antenna array is configured to transmit RF pulses into the target region of the object or internal organ and receive sets of NMR signals generated by hydrogen or other elements, and the NMR analytics logical circuit is configured to obtain and analyze sets of NMR signals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of and claims priority to U.S. patentapplication Ser. No. 16/178,317, filed Nov. 1, 2018, which is acontinuation of U.S. patent application Ser. No. 15/868,996, filed Jan.11, 2018, which claims priority to U.S. Provisional Application No.62/456,164, filed Feb. 8, 2017. The present application also claimspriority to U.S. Provisional Patent Application No. 62/720,300 filedAug. 21, 2018, and U.S. Provisional Application No. 67/720,349, filedAug. 21, 2018, the contents of which are incorporated herein byreference.

FIELD

The present disclosure generally relates to medical devices. Moreparticularly, the present disclosure relates to compact Nuclear MagneticResonance (“NMR”) systems and methods for in-vivo and non-invasivemeasurements of properties of a human or animal body using a unilateralmagnet.

BACKGROUND

Clinical Magnetic Resonance Imaging (MRI) is a mature medical imagingtechnology used for a number of diagnostic procedures. Typically, MRIsystems are configured to use cylindrical or C-shaped magnets (i.e., amagnetized enclosure) to create a magnetic field within the enclosure towhich Hydrogen atoms line up their nuclear spins. The MRI system maythen use a radio frequency (RF) to effectively knock the spinningHydrogen atoms off their polarization axis, and then detect a radiofrequency signal generated by the Hydrogen atoms returning back to theiraligned spin position with the magnetic field. Using this technique andcontrolled space-varying magnetic fields, an MRI can scan a human oranimal body in three-dimensions to create an internal image of thesubject, which varies in contrast based on Hydrogen content and thecharacteristics of the tissue surrounding the Hydrogen atoms. MRI canalso be used to directly or indirectly measure relative quantities ofother elements apart from Hydrogen, e.g., Sodium and Iron. MRI can alsobe used to quantify the relative amount of Hydrogen in certain moleculesof tissues, e.g. Hydrogen in fat, tissues or water.

MRI magnets tend to be large and expensive, and must be housed inspecialized facilities with non-standard power and specialized shieldingto accommodate the super-cooled magnetic coils and large magneticfields. The excessive cost and the demand for dedicated facilities makesMRI prohibitive for the majority of preventive medicine procedures,therapeutic efficacy evaluation and periodic checkups. Accordingly,while MRI may be used to facilitate diagnostic and screening proceduresaimed at measuring particular target substances within human or animalorgans, e.g., liver fat, iron, sodium, etc., the technology is costly,inefficient, and not universally accessible. Other modalities, such asultrasound, may also be used at a lower cost to measure properties ofthe target substances, but those modalities tend to be less accurate,specific, and/or reliable than MRI.

With the significant increase in metabolic syndrome incidence, it hasbecome important for internal medicine and specialist practitioners tobe able discriminate patients at highest risk for severe complications,such as type II diabetes and liver cirrhosis. These trends suggest theneed for tools for safe, non-invasive, and inexpensive assessment of,for example, liver disease. Also, it points to the advantages ofperforming periodic and accurate monitoring of clinical treatments.

Of particular interest is liver disease diagnostics. Non-alcoholic fattyliver disease (NAFLD) is the most common hepatic disorder in the UnitedStates. Some patients with NAFLD develop non-alcoholic steatohepatitis(NASH, abnormal retention of lipids), leading to cirrhosis, and theeventual need for a liver transplant. Further, a large number ofpatients with normal weight suffer from multiple aspects of metabolicsyndrome, including NAFLD and NASH. Disease recognition is often delayedin these patients, relative to obese patients, leading to more severecomplications. Also, since sarcopenia and fatty replacement is a keyfinding of metabolically obese normal-weight (MONW) subjects, a usefulapplication is tracking fat concentration in limb musculature.

Assessment of hepatic steatosis for clinical care requires diagnosis andgrading of severity. The relevant classification threshold may vary,from the standard 5% steatosis threshold defining hepatic steatosis, toa 30% threshold for sometimes used to exclude liver transplantationdonors. Accurate quantification is helpful for grading steatosis and forlongitudinal monitoring of patients.

If accurate and low cost diagnostics are readily available forquantifying fat content, early indicators could lead to a significantlyreduction of the incidence of liver disease.

Additionally, iron overload occurs in liver disease, metabolic syndromeand hereditary hemochromatosis, in hemodialysis patients receivingsupplemental iron, and in patients who receive multiple red-celltransfusions for thalassemia, sickle-cell disease (SCD), andmyelodysplastic syndrome (MDS). Iron overload can cause death from heartfailure, liver cancer, or cirrhosis, as well as diabetes, endocrinedeficiency and joint problems. It may increase risks of hepatocellularcancer in alcoholic liver disease (ALD) and NASH, exacerbate fibrosis inALD, affect insulin resistance and liver dysfunction in some patientswith metabolic syndrome, and contribute to immune dysfunction and heartfailure in hemodialysis. Together, these conditions affect millions ofpatients.

Traditional methods used to quantify iron overload are ambiguous,invasive, or expensive. Typically, clinicians infer iron status fromserum ferritin and transferrin saturation. However, these indicators areinherently ambiguous, because they are affected by liver disease,inflammation, hemolysis and other common conditions. As a result,diagnosing iron overload can be a complicated process that may includegenetic tests for hemochromatosis, and integrating multiple clinicalsigns and serum tests to rule out inflammation, liver disease and otherconfounding factors. Liver iron measurements by biopsy or MRI are moredirect and less ambiguous, but liver biopsy is invasive, while an MRIscan is expensive and not readily available in all locations.

Brief Summary of Embodiments

A low cost, compact Nuclear Magnetic Resonance (NMR) instrumentexamining specific volumes in the body provides valuable and qualitydata comparable to data generated by MRI, but at the cost of simplerportable clinical instruments such as ultrasound machines.

Embodiments of the disclosed technology provide a compact flat, tapered,or curved unilateral probe to inspect human or animal organs in-vivo andnon-invasively. In the context of the present disclosure, “unilateral”NMR probe means that the probe is open. There is no need to fullyenclose the sensitive volume with the scanning probe, as is the casewith conventional MRI magnets. The scanning probe is placed in theproximity of the body or on the body. The probe may generate a sensitivevolume outside or inside of the boundaries of the probe, as explainedhereafter. Other terms sometimes used to describe unilateral NMR probesmay be, for example, “single sided” and “open.” The term “single sided”may be used to refer to magnets that generate sensitive volumes onlyoutside of the boundaries of the magnet. For clarification, in thepresent disclosure, the sensitive volume may be beyond or within theouter boundaries of the scanning probe.

A unilateral NMR configuration enables a number of diagnostic procedureswithout utilizing large and expensive MRI devices. Of special attentionis the capability to inspect the liver, but other organs and parts ofthe body may also be inspected with the open NMR probe. This probe neednot generate an image, but merely measures properties of selectedvolumes of organs inside of the human or animal body. Spatial resolution(imaging) may be achieved by frequency or phase encoding methods. Giventhe inhomogeneity of the fields generated by open magnets, the sensitivevolume is somewhat limited and therefore imaging is of interest wheninspecting smaller features in the body. Applications such as fat oriron in the liver or sodium in skin or muscle do not require imaging,rather performing NMR measurements in a selected volume is sufficient.

The disclosed technology utilizes NMR properties of elements such asproton and sodium to address specific clinical applications. In someexamples, the disclosed technology may be used to quantify the level offat in liver or the level of sodium in tissue or blood. Of specialinterest is the diagnosis of liver disease based on the correlation to,for example, hepatic fat content.

The present disclosure provides an NMR apparatus with a compact probethat may be flat, tapered, or curved and may be positioned on or inproximity to a subject's body. The subject may be human or animal. Thecompact probe may be portable or have a relatively small footprint whencompared with commercial MRI scanners. The compact probe is alsogenerally lower cost, consumes less power, and creates a lower magneticfield than commercial MRI scanners. The NMR apparatus disclosed hereinmay generate MRI-type data for a number of unmet medical needs. Forexample, a small clinic could perform non-invasive liver examinations inminutes or seconds with an economical device with the accuracy andreliability of, e.g., an MRI system, but the footprint, portability, andrelatively low cost of an ultrasound instrument.

As an example, liver fat and iron content may be measured accuratelyusing NMR and MRI methods. With traditional MRI methods, the liver fatand iron contents are measured by analyzing the signals from selectedpixels in the liver and the distinctive response of protons in fat,water and tissues. With NMR spectroscopy and MRI spectroscopy (MRIS),the signals from protons in fat may be discriminated from signals fromsurrounding water and tissue based on the proton NMR spectrum. In thehuman and animal bodies, protons are abundant in water, in fat(triglycerides), and in other tissues. Protons may be part of fat orwater molecules and be bond to tissues or mobile (“free”).

Tissue fat comprises long carbon-chain triglycerides. Each triglyceridemolecule contains protons in different chemical environments.Neighboring nuclei in the long chains generally interact with each otherthrough a distortion of their electron clouds in a process known asJ-coupling. This J-coupling is detectable and recognizable in NMRsignals, e.g., in response to disturbing the spin axes of J-coupledprotons relative to a magnetic field using different RF pulsefrequencies. This is important for NMR-based chemical analysis becauseit enables differentiation of fat based on shifts in the spectral linesresulting from the J-coupling effect.

NMR signals may also be attained with unilateral probes, in which thesensitive volume is either inside or outside of the scanner. UnilateralNMR probes, and particularly low-magnetic field unilateral NMR probes,typically generate non-uniform magnetic fields which are not conduciveto MRIS methods.

Embodiments of the present disclosure are directed to unilateral NMRsystems that use low spectral resolution NMR techniques and apseudo-spectroscopic fat quantification method in order to accommodatethe non-uniform magnetic field generated by the unilateral NMR probe.Using multi-pulse echo train techniques, spectroscopic differentiationmay be achieved indirectly based on the specific timing of NMRmulti-pulse sequences, even in the presence of non-uniform magneticfields.

In some examples, the unilateral probe includes a unilateral magnet witha proximal surface and a distal surface, the distal surface being shapedwith a negative curvature and/or taper in order to enclose an emptyspace or cavity within the magnet's profile. The magnet may bepositioned with the distal surface against or in proximity to asubject's body as to partially enclose the subject's body, and aselected internal organ and/or region of interest, within the emptyspace inside the negative curvature of the magnet. By shaping the magnetthis way, the magnetic field may be better controlled on a sensitivevolume within the target region, resulting in high efficacy in aunilateral NMR measurement.

With low spectral resolution NMR instruments, the relative concentrationof fat may be based on multi-component relaxation and diffusionparameters attained from analysis of the NMR signals. Identifying andquantifying iron with NMR signals may be accomplished based on theeffect on relaxation times of the proton NMR signal. Iron detection andquantification may further be facilitated using multiple magnetic fieldstrengths. A correlative relationship between iron content and NMRmeasurements at varying magnetic field strengths may be generatedempirically using historical MRI and/or NMR data.

Open NMR probes provide the capability of analyzing objects that arelarger than the probe itself. An example is a broadly-used borehole NMRprobe that measures signals from water and oil in the formationssurrounding the probe. In some embodiments of the present disclosure, acompact unilateral probe may project a magnetic field, e.g., inside ahuman or animal bodies, and organs contained therein, without having toenclose or otherwise completely surround the subject with the magnet. Inother words, a unilateral NMR probe, as disclosed herein, may collectNMR signals from inside the body by simple placing a flat, tapered, orcurved probe in the proximity of the organ or region to be examined.

As an example, clinically relevant indicators such as fat or ironcontent in the liver may be determined by measurable NMR parameters. Theopen probe can identify and quantify fat, iron, sodium or othersubstances in several volumes of the organs and skeletal muscle.Embodiments of the disclosed technology may be applied to reliably andaccurately detect and monitor health issues related to iron and/or fatcontent in the liver and other organs at a low cost relative to MRI,generating accurate clinically-relevant measurements. Measurements ofthe fat or iron content may be based on singling out proton NMR signalsbased on their characteristics such as relaxation times and spectralshifts. The diffusion parameters may also be used as a discriminationfactor between the protons in fat or water and surrounding tissues.Methods disclosed herein may also be used to compute the relative andabsolute content of fat and iron in human and animal organs.

For example, by providing a simultaneous readout of iron concentrationand fat fraction, a practitioner can discriminate hyperferritinemia frommetabolic syndrome from true iron overload.

In one aspect of the present disclosure, an apparatus for measuringliver fat or iron content, or sodium or phosphorous content in muscletissue non-invasively and in-vivo using a unilateral NMR probe isdisclosed. The NMR probe may include a flat, tapered, curved, or othershaped magnet. In some embodiments, the NMR probe may include multiplemagnets affixed or located in proximity to each other to generate thedesired magnetic field shape. The magnet(s) may be permanent orelectro-magnetic in nature.

The disclosed apparatus may include a probe positioned against or in theproximity to the body. The probe may generate a sensitive volume insidethe body. The apparatus may also include an RF antenna placed between amagnet and the body or around the magnet. The antenna may be used toattain NMR signals. The probe may generate static and RF magnetic fieldsused to cause NMR response signals from selected regions and depthswithin a subject's body. The resulting NMR signals may be stored,processed, and measured to determine characteristics of the selectedregions and depth, e.g., fat and iron content within the specific volumeor at various regions inside the liver or sodium or phosphorous contentin muscle tissue. The measurement may be performed at a number ofselected specific volumes with or without repositioning the probe. Thiscould be used to determine the fat, iron, sodium or phosphorous contentat various positions in the organ of interest or to generate a profile.

The iron content may be determined indirectly, by the effect of iron inthe proton NMR relaxation time, which may be detected in the NMRresponse signal.

It should be noted that the NMR methods and systems disclosed herein,although described with reference to their applications for detectingiron or fat in the liver and sodium or phosphorous in muscles, may alsobe applied to other elements and other internal and/or external organs,e.g., the heart, lungs, brain, esophagus, salivary glands, mouth,pharynx, larynx, stomach, pancreas, bladder, intestines, kidneys,gallbladder, spleen, skeleton, blood, blood marrow, arteries, veins,lymph nodes, reproductive organs, and/or other internal and/or externalorgans in humans and/or animals. The NMR methods and systems disclosedherein may also be applied to the detection and quantifications of otherspectrographically discernable substances apart from iron and fat, e.g.,proteins, nucleic acids, carbohydrates, hydrocarbons, potassium,phosphorous, sodium, copper, and/or other metals, elements, and organicor non-organic molecules.

Other features and aspects of the invention will become apparent fromthe following detailed description, taken in conjunction with theaccompanying drawings, which illustrate, by way of example, the featuresin accordance with embodiments of the invention. The summary is notintended to limit the scope of the invention, which is defined solely bythe claims attached hereto.

BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure, in accordance with one or more variousembodiments, is described in detail with reference to the followingfigures. The drawings are provided for purposes of illustration only andmerely depict typical or example embodiments of the invention. Thesedrawings are provided to facilitate the reader's understanding of theinvention and shall not be considered limiting of the breadth, scope, orapplicability of the invention.

FIG. 1A is a schematic diagram illustrating a cross-section view of anexample unilateral NMR apparatus for in-vivo diagnostics, in accordancewith embodiments disclosed herein, with the sensitive volume outside ofthe boundaries of the apparatus.

FIG. 1B is a schematic diagram illustrating a cross-section view of anexample unilateral NMR apparatus for in-vivo diagnostics, in accordancewith embodiments disclosed herein, with the sensitive volume inside ofthe boundaries of the apparatus.

FIG. 1C is a schematic diagram illustrating a perspective view of anexample unilateral NMR apparatus for in-vivo diagnostics, in accordancewith embodiments disclosed herein.

FIG. 2A is a chart illustrating an example distribution of magneticfield amplitude along a y-axis for a unilateral NMR probe, extending outin the y-direction outward from the NMR probe, consistent withembodiments disclosed herein.

FIG. 2B is a chart illustrating an example distribution of magneticfield amplitude along the x-axis for a unilateral NMR probe, extendingalong the x-direction in the NMR probe, consistent with embodimentsdisclosed herein.

FIG. 3A is a chart illustrating an example relationship between RFfrequency and distance from the unilateral NMR antenna for an example RFexcitation and response signal, consistent with embodiments disclosedherein.

FIG. 3B is a chart illustrating example relationships between RF pulsebandwidth and distance from the unilateral NMR antenna for example RFexcitation and response signals at three different frequencies,consistent with embodiments disclosed herein.

FIG. 4A is a schematic diagram illustrating a cross-section view of anexample NMR apparatus and corresponding magnetic field distribution witha sensitive volume outside of the NMR probe, consistent with embodimentsdisclosed herein.

FIG. 4B is a schematic diagram illustrating a cross-section view of anexample NMR apparatus and corresponding magnetic field distribution witha sensitive volume within the NMR probe, consistent with embodimentsdisclosed herein.

FIG. 5 illustrates an example NMR apparatus as applied to a humansubject for purposes of measuring characteristics in the liver,consistent with embodiments disclosed herein. In this example, thesensitive volume is outside of the unilateral NMR probe.

FIG. 6 illustrates an example NMR apparatus as applied to a humansubject, consistent with embodiments disclosed herein.

FIG. 7A illustrates a perspective right-side view of an example NMRapparatus, consistent with embodiments disclosed herein.

FIG. 7B illustrates a perspective left-side view of an example NMRapparatus, consistent with embodiments disclosed herein.

FIG. 8A illustrates a perspective view of an example table-based NMRapparatus for purposes of measuring characteristics of a subject'sorgan, consistent with embodiments disclosed herein. In this example theprobe is positioned underneath the table.

FIG. 8B illustrates a top view of an example table-based NMR apparatusfor purposes of measuring characteristics of a subject's organ,consistent with embodiments disclosed herein. In this example the probeis positioned underneath the table.

FIG. 8C illustrates a side view of an example table-based NMR apparatus,with the NMR probe positioned underneath the table, for purposes ofmeasuring characteristics of a subject's organ, consistent withembodiments disclosed herein.

FIG. 8D illustrates a side view of an example table-based NMR apparatus,with the NMR probe positioned on top of the table, for purposes ofmeasuring characteristics of a subject's organ, consistent withembodiments disclosed herein.

FIG. 9A illustrates a perspective view of an example table-based NMRapparatus with the NMR probe positioned on the table for purposes ofmeasuring characteristics of an internal organ of a human subject,consistent with embodiments disclosed herein.

FIG. 9B illustrates a perspective view of an example table-based NMRapparatus with the NMR probe positioned underneath the table forpurposes of measuring characteristics of an internal organ of a humansubject, consistent with embodiments disclosed herein.

FIG. 10 is a flow chart illustrating an example process for non-invasiveand in-vivo measurement, screening, and/or diagnosis of characteristicsof a subject's organ using an open NMR apparatus, consistent withembodiments disclosed herein.

FIG. 11A is a flow chart illustrating an example process fornon-invasive and in-vivo measurement, screening, and/or diagnosis ofcharacteristics of a subject's organ using an open NMR apparatus,consistent with embodiments disclosed herein.

FIG. 11B is a chart illustrating an example time series of the amplitudeof the NMR signal in a multi-pulse sequence and a two exponential decayfitting to data collected in accordance with the process illustrated inFIG. 11A as applied to an animal liver with a high content of fat.

FIG. 12A is a chart illustrating three time series of NMR signals in amulti-pulse sequence, collected in accordance with embodiments disclosedherein, where the time between the RF pulses is changed.

FIG. 12B is a chart illustrating a change of NMR signal decay time withthe pulse spacing in a multi-pulse sequence as used to compute adiffusion parameter in accordance with embodiments disclosed herein.

FIG. 13 is a diagram illustrating an exemplary computing module that maybe used to implement any of the embodiments disclosed herein.

FIG. 14 shows examples of 2-dimensional distribution plots of T2relaxation times and diffusion parameters and T1 recovery times anddiffusion parameters, respectively.

These figures are not intended to be exhaustive or to limit theinvention to the precise form disclosed. It should be understood thatthe invention can be practiced with modification and alteration, andthat the invention be limited only by the claims and the equivalentsthereof.

DETAILED DESCRIPTION OF THE EMBODIMENTS

The present disclosure is directed towards systems and methods fornon-invasive and in-vivo measurement of characteristics of a subject'sorgan using a unilateral NMR apparatus. The subject may be human oranimal. The target organ may be a liver, heart, lungs, brain, esophagus,salivary glands, mouth, pharynx, larynx, stomach, pancreas, bladder,intestines, kidneys, gallbladder, spleen, skeleton, muscles, blood,blood marrow, arteries, veins, lymph nodes, reproductive organs, and/orother internal and/or external organs in humans and/or animals. Theelement analyzed by NMR may be hydrogen (conventional proton NMR),sodium, phosphorous, or other elements directly or indirectly observedby NMR.

In some embodiments, a medical apparatus for non-invasive and in-vivoexamination of an internal organ (e.g., a liver or muscle) includes aunilateral magnet, an RF antenna mechanically coupled to the magnet, andan NMR analytics logical circuit communicatively coupled to the RFantenna. The magnet and RF antenna together may constitute an NMR probe.The analytics logical circuit may include a processor and anon-transitory computer readable medium with computer executableinstructions embedded thereon, wherein the computer executableinstructions are configured to cause the processor to perform methodsand processes as disclosed herein.

In some embodiments, the magnet is shaped to generate a magnetic fieldthat extends unilaterally into an internal organ of a subject when themagnet is positioned against or in proximity to the subject, themagnetic field shaped to generate a sensitive volume within a targetregion of the internal organ. For example, the magnet may be flat,tapered, or curved. The magnet may comprise multiple magnetic componentsaffixed together or positioned in proximity to each other to generatethe desired magnetic field strength and distribution. The magnet may bea permanent magnet, an electromagnet, or a combination of permanentmagnet and an electromagnet. The compact magnet may be hand portable ormechanically coupled to, e.g., a pedestal, cart, table, or retractablearm.

In some examples, the RF antenna may be configured to transmit RF pulsesinto the target region of the internal organ that disturbs the spin axesof protons or other nuclei inside the target region. For example, the RFantenna may include an RF control logical circuit configured to controlpower to the RF antenna to cause the antenna to transmit desired RFfrequency pulses. The RF control logical circuit may be communicativelycoupled to an NMR probe analytical circuit, which may be configured toobtain user input (e.g., from a graphical user interface or GUI),display NMR data on the GUI, and control the RF antenna per userinstructions and preconfigured parameters.

In some examples, the RF antenna and/or RF control logical circuit maybe configured to receive a set of NMR signals. For example, an NMRsignal may be generated by a nucleus of an atom as its axis of spin isdisturbed by an RF pulse, and then realigns to a magnetic field.

In some embodiments the NMR analytics logical circuit may be configuredto obtain the set of NMR signals (e.g., a first set and a second set ofNMR signals). The NMR analytics logical circuit may further beconfigured to identify a first signal amplitude, a first T2 relaxationtime, a first T1 recovery time, and/or a first diffusion parametercorresponding to the first set of NMR signals. In some examples, the NMRanalytics logical circuit may be configured to identify a second signalamplitude, a second T2 relaxation time, a second T1 recovery time,and/or a second diffusion parameter corresponding to the second set ofNMR signals and differentiate a first substance type corresponding tothe first set of NMR signals from a second substance type correspondingto the second set of NMR signals based on distinguishing the first andsecond signal amplitudes, the first and second T2 relaxation times, thefirst and second T1 recovery times, and/or the first and seconddiffusion parameters.

In some embodiments, the NMR analytics logical circuit may be furtherconfigured to generate a J-coupling relationship between substance types(i.e., a first substance type and a second substance type present in thesensitive volume) based on a comparison of the first and second NMRsignals, and further distinguish substance types based on the J-couplingrelationship. The NMR analytics logical circuit may further configuredto determine whether one of the substance type is fat based on the T2relaxation times, the T1 recovery times, the diffusion parameter, and/orthe J-coupling relationship. The NMR analytics logical circuit may befurther configured to determine whether the substance type is iron basedon the T2 relaxation times, the T1 recovery times, the diffusionparameter, and/or the J-coupling relationship.

In some embodiments, the RF antenna may include an open coil configuredto transmit RF pulses in a substantially perpendicular orientation tothe magnetic field. The RF antenna may further include an open coilarray configured to transmit RF pulses in a substantially perpendicularorientation to the static magnetic field.

In some examples embodiments, the analytics logical circuit may beconfigured to quantify a fat concentration by applying a discretemulti-exponential signal decay model to the NMR signals.

The analytics logical circuit may be configured to plot, on the GUI, a2-dimensional distribution of the T2 relaxation times and the diffusionparameters and/or a 2-dimensional distribution of the T1 recovery timesand the diffusion parameters, as showing in FIG. 14 . In some examples,the analytics logical circuit may be configured to determine a relativefat concentration based on a ratio of signal amplitudes from amulti-exponential decay analysis (e.g., by comparing the amplitude ofthe first set of NMR signals with the amplitude of the second set of NMRsignals).

In other embodiments, the analytics logical circuit is furtherconfigured to obtain, from a NMR signal database, a calibration signalamplitude for liver fat and determine an absolute fat concentrationbased on the amplitude of the fat NMR signals as compared with thecalibration signal amplitude. For example, the NMR signal database mayinclude historical NMR signal data acquired from subjects with knownliver fat quantities and/or phantoms. In some examples, the calibrationsignal amplitude may be determined by applying a machine learning modelto a training data set, the training data set including multiplehistorical NMR signals acquired from multiple subjects and/or phantoms,and corresponding liver fat readings. The machine learning model may bea convolutional neural network (CNN), a logistical regression, adecision tree, or other machine learning algorithm.

Embodiments disclosed herein may be used to measure human and animaltissue properties for medical and veterinarian diagnostics but utilizesa compact, low cost diagnostic instrument with a probe placed against ornear by the body, in the proximity of the organ to be assessed. Variousdiagnosis procedures may be based on dedicated NMR methods utilizingunilateral probes and exploiting the inherent magnetic field gradientspresent in open magnets.

FIGS. 1A and 1B are schematic diagrams illustrating an example open NMRapparatus for in-vivo diagnostics. Referring to FIGS. 1A, 1B, and 1C anapparatus for in-vivo diagnostics may include a permanent or electromagnet 101, an RF antenna 102, and a probe enclosure 103. The figuresfurther illustrate a body of a patient 104, a sensitive volume 105, andan organ being examined 106. The magnet array may have an open and longgeometry, to accommodate placing the probe on the body or in theproximity of the body of a patient or animal. This geometry may be usedto follow a patient or animal body contour, facilitating observingorgans shallow or deep into the body.

The apparatus 100 may be placed on or near the patient, for example inthe proximity of the organ of interest (e.g., a liver, heart, lungs,brain, esophagus, salivary glands, mouth, pharynx, larynx, stomach,pancreas, bladder, intestines, kidneys, gallbladder, spleen, skeleton,muscles, blood, blood marrow, arteries, veins, lymph nodes, reproductiveorgans, and/or other internal and/or external organs). Positioning thedevice may be aided by an ultrasound device, estimating the patient'sdistance between the skin and the organ being examined. Once thedistance is determined, the unilateral probe is positioned in theproximity of the organ being examined and at a distance from the bodythat ensure the sensitive volume is inside the organ if interest. Theposition of the sensitive volume may also be controlled by changing theNMR frequency. Positioning may also be done by performing preliminaryNMR measurements observing the various tissues, generating a profile ordirectly-focusing the reading at a point deep into the body based onknowledge of the expected position of the organ.

The apparatus may use a unilateral NMR probe 100 abutted against thebody of a patient, as shown in FIG. 1A and B. In some examples, the NMRprobe 100 may be positioned in proximity to, but not abutted against thebody of the patient. The unilateral magnet 101 generates a staticmagnetic field that may be produced by a controlled-currentelectromagnet, by a permanent magnet array, or by a combination of thetwo. The apparatus 100 may include an RF antenna 102, wherein the RFantenna may include RF transmitter and receiver coils. In some examples,the RF antenna may also include an RF control logical circuit. Forexample, the RF control logical circuit may include a processor and anon-transitory medium with computer executable instructions embeddedthereon, the computer executable instructions configured to cause the RFtransmitter coils to transit RF frequency pulses in accordance withpre-determined and/or user selected protocols.

An RF field may be produced by the RF antenna in a substantiallyperpendicular direction relative to the static magnetic field generatedby the permanent or electro-magnet. In some examples, the RF antenna mayinclude multiple subcomponent RF elements, e.g., an RF antenna array.The transmit and receive coils of the RF antenna may be separateelements or a combined transmit-receive element. The unilateralpermanent magnet and the RF antenna may be configured to project safemagnetic fields into a subject's body.

In some embodiments, the unilateral magnet may generate a non-uniformmagnetic field. The non-uniform magnetic field distribution may be usedto achieve spatial selectivity and to measure diffusion parameters.Diffusion parameters help discriminates between the various tissues andwater present in a selected volume inside the human or animal body. Thefield distribution may also be controlled using controlled currentgradient coils or using shimming magnet or ferrous elements. The shapeof the magnet blocks, their magnetization level and direction, shimmingelements and gradient coils all play a role in the control of the staticmagnetic field of the unilateral probe.

Field variations in the magnetic field may be established within thesensitive volume, e.g., by varying the field generated by a unilateralelectromagnet or by repositioning a permanent or electro magnet.Additionally, measurements at more than one field may be achieved byselecting more than one volume (i.e., a different magnetic field withinthe inhomogeneous magnetic field) and assuming a low variability in ironcontent between the selected volumes.

For purposes of the present disclosure, the volume within whichmeaningful results may be produced is referred to as the sensitivevolume 105. Proton and/or other atomic nuclei spin axes within thesensitive volume will tend to align with magnetic field, i.e., line upparallel to the field direction or polarize. The atomic nuclei (e.g.,Hydrogen's proton) spin alignment may be permuted by exciting the atomicnuclei with one or a series of RF pulses generated by the RFtransmitter. In other words, the spinning nuclei are “knocked off” oftheir preferred spin axis in relation to the static magnetic field. TheRF pulses are delivered via the RF antenna 102. As the excited atomicnuclei realign to the external magnetic field, they emit RF signals(also referred to herein as NMR signals) that may be detected by the RFreceiver within the RF antenna or connected to the RF antenna 102. TheRF receiver antenna may be the same RF transmitter antenna 102 or aseparate element. The frequency of the NMR signal will be proportionalto the strength of the external magnetic field. The signal lifetimedepends on properties such as the mobility of the nucleus and thecomposition of its surrounding tissue.

In unilateral NMR, the magnet has an open configuration, such that NMRsignals are generated from a region removed from the probe 100 or withinthe probe.

The unilateral magnet in the NMR probe disclosed herein may be flat,tapered, or curved, permitting access from one side of the body, in theproximity of the organ of interest. In some examples, the NMR signal maybe obtained with a RF antenna positioned between the magnet and thepatient (as shown in FIG. 1A and B). In other examples, the RF antennamay be positioned adjacent to or otherwise near the magnet. Thepositioning of the sensitive volume will be determined by thedistribution of the static and the RF magnetic fields generated by themagnet and RF antenna and by the frequency of the excitation pulses.

FIG. 2A is a chart illustrating an example distribution of magneticfield amplitude or magnitude along a y-axis for a unilateral NMR probe,extending out in the y-direction from the NMR probe. FIG. 2B is a chartillustrating an example distribution of magnetic field amplitudeextending along the x-direction in the NMR probe, for example along oracross the gap in the magnet array shown in FIG. 1 . Referring to FIGS.2A and 2B, the size of the sensitive volume may be determined by thebandwidth of the RF pulses and the magnetic field distribution. As canbe seen in FIG. 2A, an example of the magnetic field distribution forthe unilateral NMR probe is shown. “y” represents the direction outwardsfrom the magnet, into the body. Depth Range is indicated by numeral 201,Magnetic Field Amplitude is indicated by numeral 202, and Depth ofPenetration is indicated by numeral 203. The depth range is determinedbased on the excitation frequency, which is proportional to the staticmagnetic field, the limited frequency bandwidth of the RF pulses, andthe characteristic frequency response of the NMR sequences used. Afrequency bandwidth translates into a static magnetic field range, whichin turn translates into a physical extend. The broader the pulsebandwidth, the larger the excited region. Bandwidth may also be variedby the RF pulse modulation and by the pulse sequence timing in amulti-pulse NMR protocol.

In some embodiments, the NMR probe may include a magnet array. Theconfiguration of the magnet array may be customized to generate anextended sensitive volume. This phenomenon can be observed in FIGS. 2Aand 2B in the depth direction (y) and in the direction along theextruded direction of the flat or curved magnet (x). The extended rangein any of the directions may be achieved by shimming the magnet. Aninflexion point in the field distribution 202 may be generated byincorporating secondary magnets with opposite polarity to that of theprimary magnet poles of the magnet array. This effectively subtractsmagnetic field in the proximity of the secondary magnet. The effect isless pronounced at greater distances from the secondary magnets, wherethe main pole field is dominant. The secondary magnets may then bepositioned in such way that an extended depth range is achieved.

In the direction along the magnet gap or well, an extended range may beachieved by making a longer primary magnet or by placing small gapsbetween the secondary magnets in order to modulate the shape of thefield 204. In some examples, the primary and secondary magnets may bemagnet blocks of various shapes, including cubes, rectangular prisms,triangular prisms, bars, cylinders, or trapezoidal prisms. Other shapesmay be used for both the primary and secondary magnets to achieve thedesired magnetic field distribution.

In some embodiments, the magnet may generate a magnetic field with amaximum strength ranging from about 0.03 to about 1.0 Tesla. In someexamples, field strengths between about 0.05 and about 0.5 Tesla may beused, which correspond to about 2 MHz to about 20 MHz range ofoperation. As used herein, the term “about” may indicates that therecited values may vary by as much as 5%. In some examples, the magnetblocks forming the magnet array may include materials such as NdFeB orSmCo. Alloys based on SmCo may be used to build magnets with lowtemperature coefficient. Low temperature coefficient may be used toreduce field drift due to temperature changes, which may cause changesto the shape and/or position of the sensitive volume. The temperatureaffects may be accounted for by shifting the RF frequency, controllingthe temperature of the magnet, or repositioning the probe if the shiftis significant. The temperature coefficient of NdFeB permanent magnetsis about 0.1%/C at room temperature. The temperature-driven field driftis smaller for SmCo.

To accommodate different organs, subject body sizes and ages, and othervariations in the target sensitive volume, the NMR probe may becustomized in size, shape, field strength, and other parameters for aspecific depth of penetration and sensitive volume shape and size. Forexample, with a monotonically decreasing field, the deeper the examinedregion the lower the field and the frequency.

The extension and position of the sensitive volume may be changed byfrequency encoding using a single, broadband excitation pulse or aseries of pulses with different frequencies. FIG. 3A illustrates anexcitation of a depth of interest with a single, broadband RF pulse. Thefrequency (f) dependency with depth (y) is determined by thedistribution of the static magnetic field. FIG. 3B illustrates anexcitation of the depth of interest with three RF pulses of slightlydifferent frequency. The frequency (f) dependency with depth (y) isdetermined by the distribution of the static magnetic field change insensitive volume. Numeral 301 indicate Frequency Response, Depth ofPenetration is indicated by numeral 302, Frequency is indicated bynumeral 303, and Bandwidth is indicated by numeral 304.

A stronger RF pulse with a shorter duration may be used to generate alarger sensitive volume range. In such examples, the RF antenna may beconfigured to accommodate broadband pulses, the RF pulse field strengthmay be on the order of about 1 Gauss, or 0.0001 Tesla, and the RF pulsedurations may be on the order of about 5 microseconds to about 200microseconds. The quality factor (Q) of the probe is a measure of theelectromagnetic response bandwidth of a resonant circuit. A relativelylow Q probe may be used for broad bandwidth pulses. A switching RFamplifier (e.g., H-bridge or Class D transmitters) may be used toaccommodate short duration RF pulses, which are beneficial ininhomogeneous fields.

The he sensitive volume may be represented by the relationship Δy (2π/γ)(tp δBz/δy)⁻¹, where tp is the RF pulse duration, z is the direction ofthe static magnetic field-across the probe head top- and y is thedirection away from the probe. As the excited volumes become thinner,the effective filling factor of the probe decreases. This reduces thesensitivity during data acquisition.

The signal-to-noise-ratio (SNR) for an RF coil at temperature Tc,generating a B₁ RF field and with resistance rc may be represented bythe relationship,

${SNR\alpha\frac{B_{1}/I}{\sqrt{{rsTs} + {rcTc}}}{VM}\sqrt{to}},$

where V is the excited volume, I is the current necessary to generateB1, rs and Ts are the sample resistance and temperature, respectively. Mis the transverse magnetization at the observation time tc. As the coildiameter of an open loop antenna is decreased, the RF field per unitcurrent increases approximately linearly and the sample resistancedecreases as the power of three.

To control the location of the sensitive volume within the organ ofinterest, the NMR probe may be repositioned to alter the gap between thebody and the probe, the RF frequency may be adjusted to excite adifferent region as the field is non-uniform and proportional to thefrequency, and/or the magnetic field strength may be changed.Positioning of the NMR probe may also be assisted by an ultrasound scanor by using known anatomy.

In some examples, the NMR probe may be configured to measure ironcontent. In such examples, the NMR signals may be measured at a singleor various magnetic fields. Controlled-field electromagnet orrepositionable permanent magnets may be used for the iron contentmeasurement.

FIG. 4 illustrates a cross-section view of an example unilateral NMRapparatus and corresponding magnetic field distribution. Referring toFIG. 4 , a configuration using two tapered permanent magnet blocks withopposite magnet orientations is shown. The example NMR probe may includemagnet block 401 and RF antenna 403 configured with magnetic blockorientation 402 and RF field orientation 404 to generate a sensitivevolume 405. The magnetic field distribution 406 permeates the sensitivevolume 405. For example, a “dipole” magnet array may be two blocks inopposite magnetization orientation on a ferromagnetic plate or yoke. Thefield distribution may be manipulated by the shape, magnetization,and/or orientation of the magnet blocks. Further changes in the fielddistribution may be achieved by using a set of gradient coils, a seriesof adjusting (or shimming) ferromagnetic “bottoms” or by placing anadditional piece of magnet in the gap of the magnet pair. The permanentmagnets may be optimized in shape and magnetization level of thepermanent magnet blocks, to achieve a strong static magnetic field abovethe magnet array with a relatively low field gradient in the region ofinterest.

The field of such opposite-block configuration may be primarily parallelto the outer surface of the probe. The probe configuration may beoptimized to produce flat surfaces of constant magnetic field amplitude.This has an advantage in terms of definition of a disc-shaped sensitivevolume and helps on the accurate computation of diffusion parameters.The quantification of diffusion parameters may assist providinginformation on the mobility of the protons, thus helping discriminatebetween protons in various substances such as fat, water, and tissues.

In some examples, the RF antenna 405 may be a loop or spiral coil placedabove or in the gap of the magnet array. The RF antenna may also beplaced adjacent to or near the magnet. In that case, the magnet blocksmay be made with a non-conducting bonding material in order to avoidinterference with the RF antenna due to conductivity of the magneticblocks. A RF antenna array may provide an effective way to transmit andreceive signals to and from the sensitive volume.

The unilateral antenna may have a low Q factor to account for theconductivity of the subject's organic tissue. The RF antenna may beretuned manually or automatically after the probe is placed on or closeto the body, correcting for tuning shifts generated by the presence ofthe electrical conductivity of the body. In some examples, an E-fieldshield may be used between the antenna and the body to minimize electricloading of the antenna 407.

FIG. 4A shows a configuration where the sensitive volume 405 is outsidethe boundaries of the unilateral probe. While FIG. 4B shows aconfiguration where the sensitive volume 405 is inside the boundaries ofthe unilateral probe.

FIG. 5 is an example representation of the positioning of the unilateralNMR probe in the proximity of a human liver. As shown, the sensitivevolume of the unilateral NMR probe is outside of the probe and in theliver. As illustrated in FIG. 5 , a unilateral magnet array 501 togetherwith RF Antenna 502 may generate sensitive volume 503 in liver 505.

In some embodiments, a method of taking non-invasive and in-vivomeasurements of a subject's organs using a unilateral NMR probe mayinclude placing the NMR probe on or near by the body, in the proximityof the organ of interest. A scan may be performed while keeping thecompact probe in place, without the need to apply pressure on the skin.The scan may be performed at a single, selected depth or a depth profileis manually or automatically attained (e.g., as shown in FIG. 3 ), bychanging the frequency (proportional to the static magnetic field) orrepositioning the probe.

Depth resolution may be attained by frequency encoding the acquiredsignal using a single, broadband excitation pulse or by using a seriesof pulses with different frequencies. The NMR probe may generate staticand RF magnetic fields in a manner that NMR measurements are performedat selected depths into the body. The measurement may be performed at asingle position and with a single frequency, determining properties ofan organ at a specific volume inside of it. Measurements may also beperformed at various frequencies in a single position (for example bychanging the field strength generated by a magnet) to determine the ironcontent.

The time series of the NMR signal when using a sequence of RF pulses maybe used to determine NMR relaxation times, diffusion parameters, andspectral discrimination. For example, the fat content may be determinedby quantifying the relative amount of protons in fat to proton in waterand other tissues (measurable by NMR). The quantification may beachieved by discriminating the NMR signals based on any or a combinationof: relaxation times T1 (longitudinal or spin-lattice relaxation), T2(transverse or spin-spin relaxation), diffusion parameters andJ-coupling. The use of diffusion parameters may improve discriminationbetween the various tissues and water present in the sensitive volume.

In unilateral NMR, the NMR parameters may be measured in the presence ofmagnetic field gradients. Various pulse sequences may be used to measurebiological, chemical, and physical properties of the tissue. Forexample, proton density, relaxation times, and diffusion parameters maybe quantified with spin echo pulse sequences, which are effective evenin the presence of inhomogeneous magnetic fields. Additionally,discrimination may be achieved using a dedicated J-coupling fatquantification pulse sequence. In fat suppression methods, the pulsespacing and pulse duration may be used to selectively reduce signalbased on the proton spectral shift.

In some examples, the ratio of the number of protons of mobiletriglycerides and the number of protons of mobile water and mobiletriglycerides, or Proton Density Fat Fraction (PDFF), may be used toassist with the determination of liver fat content. PDFF may bedetermined based on a discrete multi-exponential analysis of theamplitude of the NMR signals. Differentiation of liver fat from othermolecules may be based on different relaxation times of proton NMRsignals from fat, water, and tissues. PDFF may be used as a biomarker oftissue fat concentration. Other ways of representing relative fatcontent may be used, such as the relative amplitude of signals from fatto water protons. These methods enable quantification of fat and ironcontent, without utilizing spectral information.

NMR signal amplitude is a measure of the proton density in the sensitivevolume. For organs such as the liver, protons are present in water, fat,and surrounding tissues. In MRI and NMR, tissue discrimination may beachieved by determining the signal amplitude and characteristicslifetime (or relaxation time) of a multi-component signal, e.g., theaggregate of two or three exponential decaying signals, each of whichhas its own relative contribution to the total, measurable, signal.Mathematical methods allow for the deconvolution or separation of theindividual contributions. This approach enables the quantification ofprotons from fat, water, and other tissues.

Spin-echo relaxation times in the presence of magnetic field gradientsare biased by molecular diffusion, which may be used as a discriminationfactor. Diffusion is readily measurable in the presence of inhomogeneousmagnetic fields.

Unilateral magnets may have an associated field gradient that issignificantly larger than that of clinical MRI instruments. Therefore,the present disclosure provides data acquisition performed in thepresence of inhomogeneous fields. Accordingly, the lifetime of theobserved signal or T2* is short (signals decay fast). Using spin echotechniques accommodate for the shorter observed signal. Using spin echotechniques, the NMR signals are refocused and may be observed after alonger period of time. A single spin echo may be attained with two RFpulses of calibrated durations. A sequence of multiple echoes isattained by utilizing a series of RF pulses.

The T2 relaxation time from an NMR echo train or Hahn-echo and T1relaxation time may be measured with the NMR probe disclosed herein.Embodiments disclosed herein use the diffusion parameter to provideinformation on the mobility of the protons or other nuclei in water, fatand various tissues. In the presence of field gradients, the effectivedecay time during a multi pulse sequence, e.g.,Carr-Purcell-Meiboom-Gill (CPMG)—may be represented as:

1/T2eff=1/T2+A TE ²,

where T2eff is the measured relaxation time (lifetime of the signaldecay in a time series of the spin echo or Hahn echo in a two pulsemeasurement), T2 is the spin-spin relaxation time, TE is the inter-spinecho duration (echo time), and A is a parameter determined by themagnetic field gradient (G) and the diffusion parameter (D) of theobserved tissue. If the gradient is constant over the sensitive volume,A is proportional to D G². Therefore, the signal decay along a train ofRF pulses provides information on T2 as well as diffusion. In oneembodiment, diffusion effects may be reduced by running multi-echo pulsesequences with short time windows between RF pulses. The analysisincluding diffusion may be used to accurately compute T2 in the presenceof large field gradients. If this is not taken into consideration, themeasured relaxation time in the multi-echo sequence is shorter than T2.

Performing NMR measurements at two or more TE durations allows for theindependent computation of the diffusion constant and T2, as themagnetic field gradients are known. This provides an advantage as itallows to measure decay times analytically removing the effect ofdiffusion. As an added value, the diffusion parameter may be used asanother factor to discriminate between, e.g., water, fat, and othertissues.

For a multi-component signal (e.g. protons from fat, water and others),the total signal amplitude in a time series in a CPMG sequence (orsimilar multi-pulse sequence) may be represented as a continuousdistribution of decaying signals or a discrete distribution ofindividual signals as follows:

S(t)=C ₁ e ^(−t/T2eff) ₁ +C ₂ e ^(−t/T2eff) ₂ +C ₃ e ^(−t/T2eff) ₃ + . .. +C ₀,

where t is the time along the pulse sequence, C represents the relativecontribution of each component and C₀ represents the baseline signal. Ina two component case:

S(t)=C ₁ e ^(−t/T2eff) ₁ +C ₂ e ^(−t/T2eff) ₂ +C ₀,

with 1/T2eff ₁=1/T2₁ +A ₁ TE ² and 1/T2eff ₂=1/T2₂ +A ₂ TE ².

The diffusion parameters are proportional to the corresponding A₁ and A₂parameters for each of the components. In the two-component example, adouble exponential fit to the data may generate the data used to computethe relative concentration of each component, the T2 relaxation time andthe diffusion parameters. The relative concentration of a component,such as fat, may be expressed as a ratio, C1/C2, or as the followingratios:

C ₁/(C ₁ +C ₂) and C ₂/(C ₁ +C ₂) or C ₁/(C ₁ +C ₂ +C ₀) and C ₂/(C ₁ +C₂ +C ₀).

The computation of C1 and C2 may be determined by resolving theindependent equations shown above or by resolving the various equationssimultaneously.

In other examples, a 2-dimensional (2D) map of the T2 and diffusionparameter may be plotted after using dedicated pulse sequences andanalysis. The combination of T2 and diffusion information enables thevisualization of various contributions to the signal, e.g. water, fat,and other tissues.

In some embodiments, absolute fat concentration may be determined usingthe unilateral NMR probe. For example, the NMR probe may be calibratedusing historical proton concentration data or using a normalizationfactor post processing. This method is based on the property that theshape and volume of the sensitive volume is essentially unchanged whenfrequency and RF pulses are unchanged between the calibration and themeasurement of the target organ. Corrections may be performed ifelectrical loading of the body are observed and measured during thediagnostic procedure.

By measuring the relative amplitude of protons in fat signals andprotons in water, the fat-to-water ratio may be calculated. NMRmeasurements at specific depths in the body and depth profiles of NMRparameters may be used to quantify the fat content. NMR signals may alsobe observed as generated by protons in surrounding tissues. Depending onthe NMR setup, signal may be observed from bond protons, which typicallyhave a faster decay time. These signals are obscured in instruments thatdo not focus on fast decaying signals. The unilateral NMR instrument maybe furnished with a RF antenna and receiver that are capable ofdetecting fast decaying signals, allowing for the observation of protonand other elements bonded or chemically linked to various tissues andeven solid components.

The measurement of specific organ properties—e.g. fat content—may beperformed by using dedicated pulse sequences that enhances or decimatessignals with specific relaxation times. As an example, T1 contrast(signal bias) may be achieved by changing the repetition rate in thepulse sequence or using a single or multiple saturation pulses beforethe pulse sequence is launched.

FIGS. 6 through 9 illustrate embodiments of the disclosed technology.For example, FIGS. 6 and 7 show a compact configuration where thepatient may stand while measurements are taken with the NMR probe. Asillustrated, NMR probe head 601 may be positioned against or inproximity to a subject. User interface 602 may accept input from a userfor purposes of setting system parameters and configuring the NMR probe,and may display NMR signals and results. A height adjustment mechanism603 may enable adjustments of the NMR probe position relative to thesubject and target organ. The wheeled probe 601 may be positioned on orin proximity to the body, in the proximity of the liver or other organs.The probe 601 height may be adjusted according to the height of thepatient. The wheels 605 may be locked to avoid displacement of theinstrument while the measurements are performed.

Similarly, various views of the apparatus shown in FIG. 6 are presentedin FIG. 7 . The NMR probe 701 may be tattered to a compact control unit.The apparatus has a control console/user interface, with buttons or atouch screen that triggers a measurement.

In some embodiments of the disclosure, a permanent magnet arraygenerating magnetic fields parallel to the top of the probe head, with acontained stray field and a moderate depth gradient, may be used toattain depth profiles. The magnet array may be built with NdFeB magneticmaterial. SmCo and other magnetic alloys with adequate temperaturecharacteristics may also be used.

Example NMR probe designs may be configured for safety by keeping themagnetic field confined to a small region around the probe head. Whennot used, the NMR probe head may be completely or partially covered witha ferromagnetic or high permeability material to effectively contain themagnetic field, addressing issues of safety.

Referring to FIG. 8 and FIG. 9 , a compact probe may be mounted under abed or placed on the bed. The NMR probe may generate a sensitive volumeabove the probe or within the boundaries of the probe, in accordancewith an alternate embodiment of the present disclosure. As can be seen,a patient Table 801, a Probe Opening 802, a Probe 803, Control and DataLine 804, a Retractable Probe Cover 805, and Sensitive Volume 806 areshown. The probe 803 may be mounted under the bed or placed on the bedand the sensitive volume 806 is located above the probe. The patient 902may be positioned in a way that the area on the side of the chest—nearthe liver—is above the Probe 903, as shown in FIG. 9 . The patient Table901 may have integrated Retractable Probe Cover 905 that effectivelyblocks the magnetic field when is shut—when the apparatus is not in use.This is a safety feature that is easily incorporated using a highpermeability or ferromagnetic material that contains the magnetic fieldwhen desired. For the probe placed on the table or bed, the magnet maybe covered with a ferrous or other high permeability cover—allowing forthe probe to be safely moved or kept on the bed.

FIG. 10 illustrates an example diagnostic protocol for non-invasive andin-vivo NMR measurement using a unilateral NMR probe. For example, aliver exam may be based on fat, iron, or another exam may be based onsodium content in tissue. As illustrated, the procedure may include thepreparation of the patient at step 1001. This may include, for example,removal of the shirt and using pants free of metallic components. TheNMR probe may then prepared for the specific exam to be performed atstep 1002. This may include setting parameters to target a proper depthinto the body and selection of specific data collection protocols, forexample, using a GUI communicatively coupled to the NMR probe. Themethod may also include positioning the NMR probe on or near the body ofthe patient, by the organ being examined at step 1003. The method mayalso include taking a preliminary examination at step 1004 to assist indetermining proper positioning. If the results of the preliminary examshow issues (such as erroneous positioning), the operator may reset thepositioning of the patient and/or device parameters at step 1002.

The method may include performing the diagnostic procedure by initiatingthe data acquisition at step 1005. The data acquisition may range from asingle channel RF signal collection to dual channel RF acquisition tocollecting signal from multiple antennas in a RF antenna array. If an RFantenna array is utilized, the amplitude and phase of the signals fromeach element is measured and processed.

In some examples, the start of the exam may be as simple as pressing aSTART option on a GUI. The method may include processing acquired dataat step 1006 and storing the results. As an option, the raw data mayalso be stored for post-processing as necessary. The GUI may display theresults of the exam at step 1007. The result may, for example, be asimple value indicating the fat content in an organ such as the live. Ifproblems arise from the results or if additional data is necessary, theoperator may be re-initiate the data acquisition process at step 1008.

In some embodiments, stored data may be integrated into a medical recordor shared with medical professionals. For example, the data may betransferred to a portable device such as a flash memory stick or it maybe accessed from a remote location. Remote access may be performedwirelessly or by a wired network, for example via USB or Ethernet. Thedata may be electronically shared at step 1010 as part of the electronichealth record (EHR) and/or electronic medical record (EMR) of thepatient. The diagnostic results may be part of the medical and treatmenthistory of the patient. The format may be for example in accordance withIntegrated Laboratory Systems (ILS).

In some examples, a data bank may keep information of the clinicaldiagnostic data. The data may contain other information as age of thepatient, Body Mass Index, weight, region and others. The data bank maybe used for example to “learn” trends and managing medical risk. Theprocess to manage and analyze the data could include machine learningand artificial intelligence processing. As the “big data” bank may becontinuously fed with results from more exams, the algorithms wouldrefine the output over time, as they “learn” the efficacy of theprediction. The data bank also allows to directly compare a result withthat of other patients or groups of patients.

The availability of trend information from a data sharing approachallows for custom treatments. Also, if the data includes patients undertreatment with drugs, the information may be utilized to gauge theefficacy of drugs in the market or entering the market. Correlation maybe found between the efficacy and specific population groups.

FIG. 11 illustrates an example non-invasive in-vivo NMR examination. Asillustrated in FIG. 11A, the process may be automatically initiated ormanually-triggered at step 1101. Once the patient is in place, the RFsystem may be auto-tuned. The antenna electromagnetic characteristicsmay be affected by the presence of the electrically conductive humanbody. The instrument may quantify the effect and optimize the antennacharacteristics before starting with the power transmission and signalcollection at step 1103. In some examples, the received RF signals maybe modulated and amplified with low noise electronics. Once the signalis collected and digitized—analog or digital signal processing may alsobe performed. The signal may be conditioned at step 1105. RF filters maybe applied to the signals to discard unwanted signals that reduce theaccuracy and precision of the results. The performance may be improvedby signal averaging, which increases the signal-to-noise-ratio of thesignal. Fourier Transformation of the data (FT or Fast Fourier TransformFFT) may also help in selecting signal at the frequency of interest andadding contributions of the signal over a selected time window.

In some embodiments, a series of parameters of interest may be computedat step 1106. For example, parameters of interest may include the signalamplitude, the relaxation times (T2, T1, T2*), J-coupling and diffusioncoefficient. Typical T1 relaxation times may range from tens ofmilliseconds to the order of 1 second. T2 is generally shorter than T1.One or more parameters of interest may be correlated to clinicallyrelevant information at step 1107. For example, a multi-exponentialdecay of the NMR signal may be used to compute the relative amount offat in organisms like the liver. Processed data may be formatted andshared at step 1108. In some examples, the output of the NMR probe maybe the raw or processed NMR data, which may be analyzed at a later stageby a medical professional. In some embodiments, results may be displayedon a GUI when the exam is completed. As an example, the relative orabsolute fat content in the liver may be displayed.

As an example, FIG. 11B shows the time series of a multi-echo CPMG pulsesequence. This sequence allows manipulation RF pulse and signal phasesto effectively reduce unwanted spurious background signals and thereforeincrease signal to noise ratio.

In some instances, sensitivity may be increased, which in turn improvesprecision and accuracy, using signal averaging. For example, instead ofcollecting a single time series of the signal amplitude, the acquisitionmay be repeated several times. The data is then added or averaged. Ifthe noise is incoherent (for example white Gaussian noise), the signalto noise ratio increases approximately as the square root of the numberof scans. As one consideration to this signal averaging process, thespins from the nucleus of the atoms should significantly or fully“recover” or repolarize after each acquisition. The time scale for therepolarization is the relaxation time called T1.

In some examples, signal-to-noise ratio may be improved by collectingunwanted interfering far-field RF signals using a separate set ofantennae. The RF interference may be suppressed by mathematicallysubtracting the signals correlated to the far fields, while keeping thesignals of interest.

In some examples, signal-to-noise ratio may be improved by applyingfilters, such as match filtering or Hanning windows. The time series orthe Fourier Transform data may be modulated by the expected response.

The plot in FIG. 11B shows the amplitude of each of the echoes and adouble exponential fit to the time-series data, with a statisticalCoefficient of Determination of R²=0.97. The dual decay observed isdriven by different relaxation times for fat and for water and othertissues. The two exponential decaying signals add to the observed signaldecay. The results for the regression for three different spacingbetween RF pulses are shown in FIG. 12 . This plot shows how the effectof diffusion produces a faster decay, which is quantifiable by theanalysis presented in this disclosure. The example illustrated in FIG.11 and FIG. 12 results in a ratio of fat to water and other observabletissues of C₁/(C₁+C₂)=0.40. The diffusion parameters are computed by afitting to the data for each of the components—FIG. 12B shows thefitting using three pulse separations (or echo times). The ratio ofdiffusion parameter is calculated as D₁/D₂=A₁A₂. In this case D₁/D₂=1.7.This indicates that the fast decaying component has a diffusionparameter 70% higher than that of the slow decaying component. Theanalysis extends to more than two components.

The ratio may be corrected for diffusion effects in the presence ofinhomogeneous static magnetic fields, as explained in this disclosure.The pulse sequence with the shortest interval between RF pulses providesthe fat ratio that is closest to the corrected value, as longer pulseseparations show more pronounced diffusion effects.

As used herein, the term logical circuit or component might describe agiven unit of functionality that can be performed in accordance with oneor more embodiments of the technology disclosed herein. As used herein,a component might be implemented utilizing any form of hardware,software, or a combination thereof. For example, one or more processors,controllers, ASICs, PLAs, PALs, CPLDs, FPGAs, logical components,software routines or other mechanisms might be implemented to make up acomponent or logical circuit. In implementation, the various componentsor logical circuits described herein might be implemented as discretecomponents or the functions and features described can be shared in partor in total among one or more components or logical circuits. In otherwords, as would be apparent to one of ordinary skill in the art afterreading this description, the various features and functionalitydescribed herein may be implemented in any given application and can beimplemented in one or more separate or shared components in variouscombinations and permutations. As used herein, the term logical circuitmay describe a collection of components configured to perform one ormore specific tasks. Even though various features or elements offunctionality may be individually described or claimed as separatecomponents or logical circuits, one of ordinary skill in the art willunderstand that these features and functionality can be shared among oneor more common software and hardware elements, and such descriptionshall not require or imply that separate hardware or software componentsare used to implement such features or functionality.

Where logical circuits, components, or components of the technology areimplemented in whole or in part using software, in one embodiment, thesesoftware elements can be implemented to operate with a computing orprocessing component capable of carrying out the functionality describedwith respect thereto. One such example computing component is shown inFIG. 13 . Various embodiments are described in terms of thisexample—computing component 1300. After reading this description, itwill become apparent to a person skilled in the relevant art how toimplement the technology using other computing components orarchitectures.

Referring now to FIG. 13 , computing component 700 may represent, forexample, computing or processing capabilities found within desktop,laptop and notebook computers; hand-held computing devices (PDA's, smartphones, cell phones, palmtops, etc.); mainframes, supercomputers,workstations or servers; or any other type of special-purpose orgeneral-purpose computing devices as may be desirable or appropriate fora given application or environment. Computing component 1300 might alsorepresent computing capabilities embedded within or otherwise availableto a given device. For example, a computing component might be found inother electronic devices such as, for example, digital cameras,navigation systems, cellular telephones, portable computing devices,modems, routers, WAPs, terminals and other electronic devices that mightinclude some form of processing capability.

Computing component 1300 might include, for example, one or moreprocessors, controllers, control components, or other processingdevices, such as a processor 1304. Processor 1304 might be implementedusing a general-purpose or special-purpose processing logical circuitssuch as, for example, a microprocessor, controller, or other controllogic. In the illustrated example, processor 1304 is connected to a bus1302, although any communication medium can be used to facilitateinteraction with other components of computing component 1300 or tocommunicate externally.

Computing component 1300 might also include one or more memorycomponents, simply referred to herein as main memory 1308. For example,preferably random access memory (RAM) or other dynamic memory might beused for storing information and instructions to be executed byprocessor 1304. Main memory 1308 might also be used for storingtemporary variables or other intermediate information during executionof instructions to be executed by processor 1304. Computing component1300 might likewise include a read only memory (“ROM”) or other staticstorage device coupled to bus 1302 for storing static information andinstructions for processor 1304.

The computing component 1300 might also include one or various forms ofinformation storage devices 1310, which might include, for example, amedia drive 1312 and a storage unit interface 1320. The media drive 1312might include a drive or other mechanism to support fixed or removablestorage media 1314. For example, a hard disk drive, a floppy disk drive,a magnetic tape drive, an optical disk drive, a CD or DVD drive (R orRW), or other removable or fixed media drive might be provided.Accordingly, storage media 1314 might include, for example, a hard disk,a floppy disk, magnetic tape, cartridge, optical disk, a CD or DVD, orother fixed or removable medium that is read by, written to or accessedby media drive 1312. As these examples illustrate, the storage media1314 can include a computer usable storage medium having stored thereincomputer software or data.

In alternative embodiments, information storage mechanism 710 mightinclude other similar instrumentalities for allowing computer programsor other instructions or data to be loaded into computing component1300. Such instrumentalities might include, for example, a fixed orremovable storage unit 1322 and an interface 1320. Examples of suchstorage units 1322 and interfaces 1320 can include a program cartridgeand cartridge interface, a removable memory (for example, a flash memoryor other removable memory component) and memory slot, a PCMCIA slot andcard, and other fixed or removable storage units 1322 and interfaces1320 that allow software and data to be transferred from the storageunit 722 to computing component 1300.

Computing component 1300 might also include a communications interface1324. Communications interface 1324 might be used to allow software anddata to be transferred between computing component 1300 and externaldevices. Examples of communications interface 1324 might include a modemor softmodem, a network interface (such as an Ethernet, networkinterface card, WiMedia, IEEE 802.XX, or other interface), acommunications port (such as for example, a USB port, IR port, RS232port, Bluetooth® interface, or other port), or other communicationsinterface. Software and data transferred via communications interface1324 might typically be carried on signals, which can be electronic,electromagnetic (which includes optical) or other signals capable ofbeing exchanged by a given communications interface 1324. These signalsmight be provided to communications interface 1324 via a channel 1328.This channel 1328 might carry signals and might be implemented using awired or wireless communication medium. Some examples of a channel mightinclude a phone line, a cellular link, an RF link, an optical link, anetwork interface, a local or wide area network, and other wired orwireless communications channels.

In this document, the terms “computer program medium” and “computerusable medium” are used to generally refer to media such as, forexample, memory 1308, storage unit 1320, media 1314, and channel 1328.These and other various forms of computer program media or computerusable media may be involved in carrying one or more sequences of one ormore instructions to a processing device for execution. Suchinstructions embodied on the medium, are generally referred to as“computer program code” or a “computer program product” (which may begrouped in the form of computer programs or other groupings). Whenexecuted, such instructions might enable the computing component 1300 toperform features or functions of the disclosed technology as discussedherein.

While various embodiments of the disclosed technology have beendescribed above, it should be understood that they have been presentedby way of example only, and not of limitation. Likewise, the variousdiagrams may depict an example architectural or other configuration forthe disclosed technology, which is done to aid in understanding thefeatures and functionality that can be included in the disclosedtechnology. The disclosed technology is not restricted to theillustrated example architectures or configurations, but the desiredfeatures can be implemented using a variety of alternative architecturesand configurations. Indeed, it will be apparent to one of skill in theart how alternative functional, logical or physical partitioning andconfigurations can be implemented to implement the desired features ofthe technology disclosed herein. Also, a multitude of differentconstituent component names other than those depicted herein can beapplied to the various partitions. Additionally, with regard to flowdiagrams, operational descriptions and method claims, the order in whichthe steps are presented herein shall not mandate that variousembodiments be implemented to perform the recited functionality in thesame order unless the context dictates otherwise.

Although the disclosed technology is described above in terms of variousexemplary embodiments and implementations, it should be understood thatthe various features, aspects and functionality described in one or moreof the individual embodiments are not limited in their applicability tothe particular embodiment with which they are described, but instead canbe applied, alone or in various combinations, to one or more of theother embodiments of the disclosed technology, whether or not suchembodiments are described and whether or not such features are presentedas being a part of a described embodiment. Thus, the breadth and scopeof the technology disclosed herein should not be limited by any of theabove-described exemplary embodiments.

Terms and phrases used in this document, and variations thereof, unlessotherwise expressly stated, should be construed as open ended as opposedto limiting. As examples of the foregoing: the term “including” shouldbe read as meaning “including, without limitation” or the like; the term“example” is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof; the terms “a” or“an” should be read as meaning “at least one,” “one or more” or thelike; and adjectives such as “conventional,” “traditional,” “normal,”“standard,” “known” and terms of similar meaning should not be construedas limiting the item described to a given time period or to an itemavailable as of a given time, but instead should be read to encompassconventional, traditional, normal, or standard technologies that may beavailable or known now or at any time in the future. Likewise, wherethis document refers to technologies that would be apparent or known toone of ordinary skill in the art, such technologies encompass thoseapparent or known to the skilled artisan now or at any time in thefuture.

The presence of broadening words and phrases such as “one or more,” “atleast,” “but not limited to” or other like phrases in some instancesshall not be read to mean that the narrower case is intended or requiredin instances where such broadening phrases may be absent. The use of theterm “component” does not imply that the components or functionalitydescribed or claimed as part of the component are all configured in acommon package. Indeed, any or all of the various components of acomponent, whether control logic or other components, can be combined ina single package or separately maintained and can further be distributedin multiple groupings or packages or across multiple locations.

Additionally, the various embodiments set forth herein are described interms of exemplary block diagrams, flow charts and other illustrations.As will become apparent to one of ordinary skill in the art afterreading this document, the illustrated embodiments and their variousalternatives can be implemented without confinement to the illustratedexamples. For example, block diagrams and their accompanying descriptionshould not be construed as mandating a particular architecture orconfiguration.

1-40. (canceled)
 41. An RF circuit for a NMR apparatus, the circuitcomprising: a transceiver to: transmit RF pulses into the target region;receive a first set of NMR signals generated by a first set of atomicnuclei from a first substance as the first set of nuclei realign theirspin axes to the magnetic field after being stimulated by the RF pulses;receive a second set of NMR signals generated by a second set of atomicnuclei from a second substance as the second set of nuclei realign theirspin axes to the magnetic field after being stimulated by the RF pulses;and a processor to: obtain the first and second sets of NMR signals;perform a discrete multi-component analysis of the NMR signals todetermine a first set of NMR relaxation times and a first diffusionparameter from the first set of NMR signals, and a second set of NMRrelaxation times and a second diffusion parameter from the second set ofNMR signals; and characterize the first and second substances based on amulti-component analysis of the NMR signals by performing a J-couplinganalysis of the NMR signals based on a distinctive response of the firstset of NMR signals and the second set of NMR signals to RF pulsesequences with pulse spacings determined by the characteristic timescale of the J-coupling; and
 42. The circuit of claim 41, wherein theprocessor is further configured to quantify a concentration of the firstsubstance based on a discrete multi-component signal decay analysis ofthe first and second NMR signals.
 43. The circuit of claim 41, furthercomprising RF antenna comprises an open coil and is configured totransmit RF pulses in a substantially perpendicular orientation to thestatic magnetic field.
 44. The circuit of claim 43, wherein the RFantenna further comprises an array of sub-antennas.
 45. The circuit ofclaim 44, wherein the processor is further configured to calculate andto plot, on a graphical user interface, a 2-dimensional distribution ofT2 relaxation times and diffusion parameters from the first and secondsets of NMR signals.
 46. The circuit of claim 41, wherein the processoris further configured to calculate and to plot, on a graphical userinterface, a 2-dimensional distribution of T1 recovery times anddiffusion parameters from the first and second sets of NMR signals. 47.The circuit of claim 41, wherein the processor circuit is furtherconfigured to determine a fat concentration based on a ratio of theamplitude of the first set of NMR signals as compared with the amplitudeof the second set of NMR signals.
 48. The circuit of claim 41, whereinthe processor circuit is further configured to detect liver fibrosisbased on a ratio of the amplitude of the first set of NMR signals ascompared with the amplitude of the second set of NMR signals.
 49. Thecircuit of claim 41, wherein the processor is further configured toobtain, from a NMR signal database, a calibration signal amplitude forfat in an organ and determine an absolute fat concentration based on aratio of the amplitude of the first set of NMR signals as compared withthe calibration signal.
 50. An NMR detection method comprising:transmitting RF pulses into the target region; receiving a first set ofNMR signals generated by a first set of atomic nuclei from a firstsubstance as the first set of nuclei realign their spin axes to themagnetic field after being stimulated by the RF pulses; receiving asecond set of NMR signals generated by a second set of atomic nucleifrom a second substance as the second set of nuclei realign their spinaxes to the magnetic field after being stimulated by the RF pulses; anda processor to: obtaining the first and second sets of NMR signals;characterizing the first and second substances based on amulti-component analysis of the NMR signals; and performing a discretemulti-component analysis of the NMR signals by determining a first setof NMR relaxation times and a first diffusion parameter from the firstset of NMR signals, and a second set of NMR relaxation times and asecond diffusion parameter from the second set of NMR signals; whereinperforming the substance characterization comprises performing aJ-coupling analysis of the NMR signals based on a distinctive responseof the first set of NMR signals and the second set of NMR signals to RFpulse sequences with pulse spacings determined by the characteristictime scale of the J-coupling.
 51. The method of claim 50, furthercomprising quantifying a concentration of the first substance based on adiscrete multi-component signal decay analysis of the first and secondNMR signals.
 52. The method of claim 50, further comprising transmittingRF pulses in a substantially perpendicular orientation to the staticmagnetic field.
 53. The method of claim 50, further comprisingcalculating and plotting, on a graphical user interface, a 2-dimensionaldistribution of T2 relaxation times and diffusion parameters from thefirst and second sets of NMR signals.
 54. The method of claim 50,further comprising calculating and plotting, on a graphical userinterface, a 2-dimensional distribution of T1 recovery times anddiffusion parameters from the first and second sets of NMR signals. 55.The method of claim 50, further comprising determining a fatconcentration based on a ratio of the amplitude of the first set of NMRsignals as compared with the amplitude of the second set of NMR signals.56. The method of claim 50, further comprising detecting liver fibrosisbased on a ratio of the amplitude of the first set of NMR signals ascompared with the amplitude of the second set of NMR signals.
 57. Themethod of claim 50, further comprising obtaining, from a NMR signaldatabase, a calibration signal amplitude for fat in an organ anddetermine an absolute fat concentration based on a ratio of theamplitude of the first set of NMR signals as compared with thecalibration signal.